The aim of this proposal is to investigate sex differences in social interaction behavior and to examine the role of the immediate early gene zif268 in the medial prefrontal cortex (mPFC) in mediating these behaviors in male and female rats. Another focus of this study is to determine the upstream and downstream molecular targets of zif268 that are relevant to sex differences in social interaction. Our preliminary data show that male rats exhibit higher social interaction (SI) than female rats -regardless of their estrus cycle-. Interestingly, the basal expression of zif268 in the medial prefrontal cortex (mPFC) varied between the sexes in that males had higher levels of zif268 expression in this region when compared to females. Through the use of zif268 antisense oligodeoxynucleotides (zif268 ASO), we induced a temporary down-regulation of zif268 expression in the mPFC of male rats and compared their SI behavior to both control males and females infused with zif268 missense oligodeoxynucleotides (zif268 MSO). Upon doing this, we found that zif268 ASO males displayed significantly less SI (and therefore, were more anxious) than control males and, in fact, displayed levels of SI which were similar to control females. In essence, down-regulation of zif268 expression in the mPFC of male rats eliminated the sex differences previously found in anxiety-like behavior in the SI test. Our novel findings have led us to hypothesize that sexually-dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety-like behavior in the SI test, which has a strong social component. In this application we would like to explore further the hypothesis that zif268 in the medial prefrontal cortex play a major role in determining sex differences in social interaction and determine the upstream and downstream targets of zif268 in the mPFC that play a major role in these sex differences in anxiety. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to investigate sex differences in social interaction behavior and to examine the role of the immediate early gene zif268 in the medial prefrontal cortex (mPFC) in mediating these behaviors in male and female rats. Our preliminary data implicate zif268 in sex differences in anxiety and led us to hypothesize that sexually-dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety. In this application we would like to explore further the hypothesis that zif268 in the medial prefrontal cortex play a major role in determining sex differences in anxiety and determine the upstream and downstream targets of zif268 in the mPFC that play a major role in these sex differences in anxiety.